p21-activated kinase (PAK) proteins are serine/threonine protein kinases homologous to the yeast Ste20 kinase. Several distinct members of the PAK family have been identified in mammalian cells, including PAK1, PAK2, PAK3, and PAK65. It has been shown that PAK proteins can be activated by the small Rho-family GTP-binding proteins Cdc42 and Rac1, which are known to regulate assembly of the actin cytoskeletal structure (Zhang et al. 1995, J. Biol. Chem. 270:23934-36).
Smooth muscle, in contrast to striated muscle (cardiac and skeletal muscle), is capable of maintaining force at low levels of intracellular calcium. One member of the small Rho-family of GTP-binding proteins, RhoA, has been shown recently to induce smooth muscle contraction independently of calcium. RhoA activates a serinet reonine kinase named ROK (RhoA associated kinase or p160ROK) which can cause smooth muscle calcium-independent contraction. Cardiac muscle, on the other hand, requires increased levels of intracellular calcium for contraction.
Smooth muscle is found in blood vessels, the airways of the lungs, the gastro-intestial tract, the uterus and the urinary tract. The uncontrolled contraction of smooth muscle in such tissues is involved in states such as hypertension (a known risk factor for heart disease), asthma, irritable bowel syndrome, incontinence or menstrual cramps. Hypertension or high blood pressure, is the most common disease affecting the heart and blood vessels. Statistics indicate that hypertension afflicts one out of every five American adults. Asthma is a chronic disease characterized by airway hyperactivity, it occurs in 5-8% of the U.S. population, and is an extraordinarily common cause of pulmonary impairment. Irritable bowel syndrome is a common syndrome characterized by frequently alternating constipation and diarrhea, usually with abdominal pain. Often stress induced, it is also caused by such physical factors as spicy foods, lack of dietary fiber, and excessive caffeine consumption. Incontinence is the lack of voluntary control over micturition. In infants it is normal because neurons to the external sphincter muscle are not completely developed. In the adult it may occur as a result of unconsciousness, injury to the spinal nerves controlling the urinary bladder, irritation due to abnormal constituents in urine, disease of the urinary bladder and inability of the detrusor muscle to relax due to emotional stress. Menstrual cramping is a painful spasmodic contraction of the uterine muscles.
Abnormal contraction in cardiac muscle is the basis of many heart diseases. Heart failure (HF) is a common heart disease caused mainly by coronary artery disease and hypertension. Because specific treatment is not possible for most patients, current therapies are designed to ameliorate the symptoms and/or forestall myocardial damage. This includes increasing myocardial contractility by increasing cardiac myofilament sensitivity to calcium (Nielsen, J. E. et al. 1995, J. Cardiovasc. Phormacol. 26:S77-S84). Changes in calcium sensitivity also occur with acute disease states including myocardial stunning. Stunning is a reversible mild form of ischemic (no blood flow) damage, and may be induced by physiological insult such as heart surgery. Severe ischemic damage occurs with myocardial infarction and results in changes to cardiac muscle function.
To date, treatments of the above mentioned states in smooth and cardiac muscle have not been completely effective.